The subject invention relates to certain novel analogs of the naturally occurring prostaglandins. Specifically, the subject invention relates to novel Prostaglandin F analogs. The subject invention further relates to methods of using said novel Prostaglandin F analogs. Preferred uses include methods of treating bone disorders and glaucoma.
Naturally occurring prostaglandins (PGA, PGB. PGE, PGF, and PGI) are C-20 unsaturated fatty acids. PGF2a, the naturally occurring Prostaglandin F in humans, is characterized by hydroxyl groups at the C9 and C11 positions on the alicyclic ring, a cis-double bond between C5 and C6, and a trans-double bond between C13 and C14. Thus PGF2a, has the following formula: 
Analogs of naturally occurring Prostaglandin F have been disclosed in the art. For example, see U.S. Pat. No. 4,024,179 issued to Bindra and Johnson on May 17, 1977; German Patent No. DT-002,460,990 issued to Beck, Lerch, Seeger, and Teufel published on July 1, 1976; U.S. Pat. No. 4,128,720 issued to Hayashi, Kori, and Miyake on Dec. 5, 1978; U.S. Pat. No. 4,011,262 issued to Hess, Johnson, Bindra, and Schaaf on Mar. 8,. 1977; U.S. Pat. No. 3,776,938 issued to Bergstrom and Sjovall on Dec. 4, 1973; P. W. Collins and S. W. Djuric, xe2x80x9cSynthesis of Therapeutically Useful Prostaglandin and Prostacyclin Analogsxe2x80x9d, Chem. Rev. Vol. 93 (1993), pp. 1533-1564; G. L. Bundy and F. H. Lincoln, xe2x80x9cSynthesis of 17-Phenyl-18,19,20-Trinorprostaglandins: I. The PG1 Seriesxe2x80x9d, Prostaglandins, Vol. 9 No. 1 (1975), pp. 1-4; W. Bartman, G. Beck, U. Lerch, H. Teufel, and B. Scholkens, xe2x80x9cLuteolytic Prostaglandins: Synthesis and Biological Activityxe2x80x9d, Prostaglandins, Vol. 17 No. 2 (1979), pp. 301-311; C. liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, xe2x80x9cDerivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2xcex1 isopropyl Ester: Potential Antiglaucoma Agentsxe2x80x9d, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
Naturally occurring prostaglandins are known to possess a wide range of pharmacological properties. For example, prostaglandins have been shown to: relax smooth muscle, which results in vasodilatation and bronchodilatation, to inhibit gastric acid secretion, to inhibit platelet aggregation, to reduce intraocular pressure, and to induce labor. Although naturally occurring prostaglandins are characterized by their activity against a particular prostaglandin receptor, they generally are not specific for any one prostaglandin receptor. Therefore, naturally-occurring prostaglandins are known to cause side effects such as inflammation, as well as surface irritation when administered systemically. It is generally believed that the rapid metabolism of the naturally occurring prostaglandins following their release in the body limits the effects of the prostaglandin to a local area. This effectively prevents the prostaglandin from stimulating prostaglandin receptors throughout the body and causing the effects seen with the systemic administration of naturally occurring prostaglandins.
Prostaglandins, especially prostaglandins of the E series (PGE), are known to be potent stimulators of bone resorption. PGF2xcex1 has also been shown to be a stimulator of bone resorption but not as potent as PGE2. Also, it has been demonstrated the PGF2xcex1 has little effect on bone formation as compared to PGE2. It has been suggested that some of the effects of PGF2xcex1 on bone resorption, formation and cell replication may be mediated by an increase in endogenous PGE2 production.
In view of both the wide range of pharmacological properties of naturally occurring prostaglandins and of the side effects seen with the systemic administration of these naturally occurring prostaglandins, attempts have been made to prepare analogs to the naturally occurring prostaglandins that are selective for a specific receptor or receptors. A number of such analogs have been disclosed in the art. Though a variety of prostaglandin analogs have been disclosed, there is a continuing need for potent, selective prostaglandin analogs for the treatment of a variety diseases and conditions.
The invention provides novel PGF analogs. In particular, the present invention relates to compounds having a structure according to the following formula: 
wherein R1, X, and Z are defined below.
This invention also includes optical isomers, diastereomers and enantiomers of the formula above, and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof.
The compounds of the present invention are useful for the treatment of a variety of diseases and conditions, such as bone disorders and glaucoma. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for bone disorders and glaucoma using theses compounds or the compositions containing them.
Terms and Definitions
xe2x80x9cAlkylxe2x80x9d is a saturated or unsaturated hydrocarbon chain having 1 to 18 carbon atoms, preferably 1 to 12, more preferably I to 6, more preferably still 1 to 4 carbon atoms. Alkyl chains may be straight or branched. Preferred branched alkyl have one or two branches, preferably one branch. Preferred alkyl are saturated. Unsaturated alkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated alkyl have one or two double bonds or one triple bond, more preferably one double bond. Alkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted alkyl are mono-, di-, or trisubstituted. The substituents may be lower alkyl, halo, hydroxy, aryloxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, and amino.
xe2x80x9cLower alkylxe2x80x9d is an alkyl chain comprised of 1 to 6, preferably 1 to 3 carbon atoms.
xe2x80x9cAromatic ringxe2x80x9d is an aromatic hydrocarbon ring. Aromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic aromatic rings contain from about 5 to about 10 carbon atoms, preferably from 5 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Bicyclic aromatic rings contain from 8 to 12 carbon atoms, preferably 9 or 10 carbon atoms in the ring system. Bicyclic aromatic rings include ring systems wherein one ring in the system is aromatic. Preferred bicyclic aromatic rings are ring systems wherein both rings in the system are aromatic. Aromatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred aromatic rings include naphthyl and phenyl. The most preferred aromatic ring is phenyl.
xe2x80x9cCarbocyclic aliphatic ringxe2x80x9d is a saturated or unsaturated. hydrocarbon ring. Carbocyclic aliphatic rings are not aromatic. Carbocyclic aliphatic rings are monocyclic. Carbocyclic aliphatic rings contain from about 4 to about 10 carbon atoms, preferably from 4 to 7 carbon atoms, and most preferably from 5 to 6 carbon atoms in the ring. Carbocyclic aliphatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred carbocyclic aliphatic rings include cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. More preferred carbocyclic aliphatic rings include cyclohexyl, cycloheptyl, and cyclooctyl.
xe2x80x9cHaloxe2x80x9d is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred are chioro and fluoro, especially fluoro.
xe2x80x9cHaloalkylxe2x80x9d is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents; Preferred haloalkyl are C1-C12; more preferred are C1-C6; more preferred still are C1-C3. Preferred halo substituents are fluoro and chloro. The most preferred haloalkyl is trifluoromethyl.
xe2x80x9cHeteroalkylxe2x80x9d is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 1 to 18 member atoms (carbon and heteroatoms) in the chain, preferably 1 to 12, more preferably 1 to 6, more preferably still 1 to 4. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more double bonds and/or one or more triple bonds. Preferred unsaturated heteroalkyl have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or trisubstituted. The substituents may be lower alkyl, halo, hydroxy, aryloxy (e.g., phenoxy), acyloxy (e.g., acetoxy), carboxy, monocyclic aromatic ring (e.g., phenyl), monocyclic heteroaromatic ring, monocyclic carbocyclic aliphatic ring, monocyclic heterocyclic aliphatic ring, and amino.
xe2x80x9cLower heteroalkylxe2x80x9d is a heteroalkyl chain comprised of 1 to 6, preferably 1 to 3 member atoms.
xe2x80x9cHeteroaromatic ringxe2x80x9d is an aromatic ring containing carbon and from 1 to about 4 heteroatoms in the ring. Heteroaromatic rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaromatic rings contain from about 5 to about 10 member atoms (carbon and heteroatoms), preferably from 5 to 7, and most preferably from 5 to 6 in the ring. Bicyclic heteroaromatic rings include ring systems wherein only one ring in the system is aromatic. Preferred bicyclic heteroaromatic rings are ring systems wherein both rings in the system are aromatic. Bicyclic heteroaromatic rings contain from 8 to 12 member atoms, preferably 9 or 10 in the ring. Heteroaromatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo, haloalkyl, and phenyl. Preferred monocyclic heteroaromatic rings include thienyl, thiazolo, purinyl, pyrimidyl, pyridyl, and furanyl. More preferred monocyclic heteroaromatic rings include thienyl, furanyl, and pyridyl. The most preferred monocyclic heteroaromatic ring is thienyl. Preferred bicyclic heteroaromatic rings include benzo[xcex2]thiazolyl, benzo[xcex2]thiophenyl, quinolinyl, quinoxalinyl, benzo[xcex2]furanyl, benzimidizolyl, benzoxazolyl, indolyl, and anthranilyl. More preferred bicyclic heteroaromatic rings include benzo[xcex2]thiazolyl, benzo[xcex2]thiophenyl, and benzoxazolyl.
xe2x80x9cHeteroatomxe2x80x9d is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
xe2x80x9cHeterocyclic aliphatic ringxe2x80x9d is a saturated or unsaturated ring containing carbon and from 1 to about 4 heteroatoms in the ring, wherein no two heteroatoms are adjacent in the ring and no carbon in the ring that has a heteroatom attached to it also has a hydroxyl, amino, or thiol radical attached to it. Heterocyclic aliphatic rings are not aromatic. Heterocyclic aliphatic rings are monocyclic. Heterocyclic aliphatic rings contain from about 4 to about 10 member atoms (carbon and heteroatoms), preferably from 4 to 7 member atoms, and most preferably from 5 to 6 member atoms in the ring. Heterocyclic aliphatic rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. The substituents may be halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents include halo and haloalkyl. Preferred heterocyclic aliphatic rings include piperzyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl and piperdyl.
xe2x80x9cPhenylxe2x80x9d is a monocyclic aromatic ring which may or may not be substituted with from about 1 to about 4 substituents. The substituents may be fused but not bridged and may be substituted at the ortho, meta or para position on the phenyl ring, or any combination thereof. The substituents may be halo, acyl, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, phenoxy or any combination thereof. Preferred substituents on the phenyl ring include halo and haloalkyl. The most preferred substituent is halo. The preferred substitution pattern on the phenyl ring is ortho or meta. The most preferred substitution pattern on the phenyl ring is meta.
Compounds
The subject invention involves compounds having the following structure: 
In the above structure, R1 is CO2H, C(O)NHOH, CO2R2, CH2OH, S(O)2R2, C(O)NHR2, C(O)NHS(O)2R2, or tetrazole; wherein R2 is alkyl, heteroalkyl, carbocyclic aliphatic ring, heterocyclic aliphatic ring, monocyclic aromatic ring, or monocyclic heteroaromatic ring and R3 is lower alkyl, lower heteroalkyl, or haloalkyl. Preferred R2 is methyl, ethyl, and isopropyl. Preferred R1 is CO2H, C(O)NHOH, CO2R2, C(O)NHS(O)2R2, and tetrazole. Most preferred R1 is CO2H and CO2R2.
In the above structure, X is CHxe2x95x90Cxe2x95x90CH, CHxe2x95x90CH, CHxe2x95x90N, C(O), or C(O)Y; wherein Y is O, S, or NH. Preferred X is CHxe2x95x90Cxe2x95x90CH, CHxe2x95x90N, C(O), and C(O)Y. X is not part of an aromatic or heteroaromatic ring system.
In the above structure, Z is an aromatic ring or a heteroaromatic ring provided that when Z is a heteroaromatic ring Z is attached via a Carbon member atom. Preferred Z is monocyclic aromatic ring. More preferred Z is furanyl, thienyl, and phenyl.
The invention also includes optical isomers, diastereomers and enantiomers of the above structure. Thus, at all stereocenters where stereochemistry is not defined (C11, C12, and C15), both epimers are envisioned. Preferred stereochemistry at all such stereocenters of the compounds of the invention mimic that of naturally occurring PGF2xcex1.
It has been discovered that the novel PGF analogs of the subject invention are useful for treating bone disorders, especially those that require a significant increase in bone mass, bone volume, or bone strength. Surprisingly, the compounds of the subject invention have been found to provide the following advantages over known bone disorder therapies: (1) An increase trabecular number through formation of new trabeculae; (2) An increase in bone mass and bone volume while maintaining a more normal bone turnover rate; and/or (3) An increase in bone formation at the endosteal surface without increasing cortical porosity.
In order to determine and assess pharmacological activity, testing of the subject compounds in animals is carried out using various assays known to those skilled in the art. For example, the bone activity of the subject compounds can be conveniently demonstrated using an assay designed to test the ability of the subject compounds to increase bone volume, mass, or density. An example of such assays is the ovariectomized rat assay.
In the ovariectomized rat assay, six-month old rats are ovariectomized, aged 2 months, and then dosed once a day subcutaneously with a test compound. Upon completion of the study, bone mass and/or density can be measured by dual energy x-ray absorptometry (DXA) or peripheral quantitative computed tomography (pQCT), or micro computed tomography (mCT). Alternatively, static and dynamic histomorphometry can be used to measure the increase in bone volume or formation.
Pharmacological activity for glaucoma can be demonstrated using assays designed to test the ability of the subject compounds to decrease intraocular pressure. Examples of such assays are described in the following reference, incorporated herein: C. liljebris, G. Selen, B. Resul, J. Sternschantz, and U. Hacksell, xe2x80x9cDerivatives of 17-Phenyl-18,19,20-trinorprostaglandin F2xcex1 Isopropyl Ester: Potential Antiglaucoma Agentsxe2x80x9d, Journal of Medicinal Chemistry, Vol. 38 No. 2 (1995), pp. 289-304.
Compounds useful in the subject invention can be made using conventional organic syntheses. Particularly preferred syntheses are carried out using the following general reaction schemes, Schemes I, II, and Ill. Scheme I describes a general reaction scheme for making compounds of the invention wherein X is CHxe2x95x90CH (Formula I) or CHxe2x95x90Cxe2x95x90CH (Formula II). Scheme II describes a general reaction scheme for making compounds of the invention wherein X is C(O) (Formula III) or C(O)Y (Formula IV). Scheme III describes a general reaction scheme for making compounds of the invention wherein X is CHxe2x95x90N (Formula V). 
In Scheme 1, R1 and Z are as defined above. The methyl 7[3-(R)-hydroxy-5-oxo-1-cyclopent-1-y] heptanoate (S1a) depicted as starting material for Scheme 1 is commercially available (such as from Sumitomo Chemical or Cayman Chemical).
In the above Scheme 1, Methyl 7-[3-(R)hydroxy-5-oxo-1-cyclopent-1-yl] heptanoate (S1a) is reacted with a silylating agent and base in a solvent that will allow the silylation to proceed. Preferred silylating agents include tert-butyldimethylsilyl chloride and tert-butyidimethylsilyl trifluoromethanesulphonate. The most preferred silylating agent is tert-butyldimethylsilyl trifluoromethanesulphonate. Preferred bases include triethylamine, trimethylamine, and 2,6-lutidine. More preferred bases include triethylamine and 2,6-lutidine. The most preferred base is 2,6-lutidine. Preferred solvents include halocarbon solvents with dichlorbmethane being the most preferred solvent. The reaction is allowed to proceed at a temperature preferably between xe2x88x92100xc2x0 C. and 100xc2x0 C., more preferably between xe2x88x9280xc2x0 C. and 80xc2x0 C., and most preferably between xe2x88x9270xc2x0 C. and 23xc2x0 C.
The resulting silylated compound is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the silyl ether is purified after isolation by distillation under vacuum.
The silylated compound is then reacted with the cuprate generated via Grignard formation of the appropriate alkenyl bromide as disclosed, for example, in the following references: H. O. House et. al., xe2x80x9cThe Chemistry of Carbanions: A Convenient Precursor for the Generation of Lithium Organocupratesxe2x80x9d, J. Org. Chem. Vol. 40 (1975) pp. 1460-69; and P. Knochel et. al., xe2x80x9cZinc and Copper Carbenoids as Efficient and Selective axe2x80x2/dxe2x80x2 Multicoupling Reagentsxe2x80x9d, J. Amer. Chem. Soc. Vol. 111 (1989) p. 6474-76. Preferred alkenyl bromides include 4-bromo-1-butene, 4-bromo-1-butyne, 4-bromo-2-methyl-1-butene, and 4-bromo-2-ethyl-1-butene. The most preferred alkenyl bromide is 4-bromo-1-butene. Preferred solvents include ethereal solvents, of which diethyl ether and tetrahydrofuran are preferred. The most preferred solvent is tetrahydrofuran. The Grignard reagent is allowed to form at a temperature between 100xc2x0 C. and 23xc2x0 C., more preferably between 85xc2x0 C. and 30xc2x0 C., and most preferably between 75xc2x0 C. and 65xc2x0 C. The reaction time is preferably between 1 hour and 6 hours, with a more preferred reaction time being between 2 hours and 5 hours, and the most preferred reaction time being between 3 hours and 4 hours.
Once the Grignard reagent is formed, the cuprate is generated from the alkenyl magnesium species. The temperature range for cuprate formation is between xe2x80x94100xc2x0 C. and 0xc2x0 C. The preferred temperature range is between xe2x88x9280xc2x0 C. and xe2x88x9220xc2x0 C. The more preferred temperature range is between xe2x88x9275xc2x0 C. and xe2x88x9250xc2x0 C. The preferred reaction time is between 30 minutes and 6 hours. The more preferred reaction time is between 45 minutes and 3 hours. The most preferred reaction time is between 1 hours and 1.5 hours.
The alkene thus formed is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the alkene is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 10% EtOAc/hexanes as the eluent. The alkene is then reacted with a hydride reducing agent and a polar, protic solvent to give the C-9 alcohol. Preferred reducing agents include lithium aluminum hydride, sodium borohydride, and L-selectride. More preferred reducing agents include sodium borohydride, and L-selectride. The most preferred reducing agent is sodium borohydride. Preferred solvents include methanol, ethanol, and butanol. The most preferred solvent is methanol. The reduction is carried out at a temperature between xe2x88x92100xc2x0 C. and 23xc2x0 C. The preferred temperature range is between xe2x88x9260xc2x0 C. and 0xc2x0 C. The most preferred temperature range is between xe2x88x9245xc2x0 C. and xe2x88x9220xc2x0 C.
The resulting alcohol is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the alcohol is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.
The resultant alcohol can be protected as described previously herein. Preferred silylating agents in this case also include tert-butyidimethylsilyl chloride and tert-butydimethylsilyl trifluoromethanesulfonate. The most preferred silylating agent is tert-butyidimethylsilyl trifluoromethanesulfonate. Preferred bases include triethylamine, trimethylamine, and 2,6-lutidine. More preferred bases include triethylamine and 2,6-lutidine. The most preferred base is 2,6-lutidine. Preferred solvents include halocarbon solvents with dichloromethane being the most preferred solvent. The reaction is allowed to proceed at a temperature preferably between xe2x88x92100xc2x0 C. and 100xc2x0 C., more preferably between xe2x88x9280xc2x0 C. and 80xc2x0 C., and most preferably between xe2x88x9270xc2x0 C. and 23xc2x0 C.
The resulting silylated compound, S1b is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, the silyl ether is purified after isolation by distillation under vacuum, giving compound S1b.
The protected alcohol is then treated with a form of osmium and sodium periodate in a solvent where they are both soluble. Preferred forms of osmium include osmium tetraoxide and potassium osmate. Preferred solvent systems include 1:1 mixtures of acetic acid and water and 1:1:2 mixtures of water, acetic acid and THF. The result of this treatment is the aldehyde, S1c.
The compound S1c is isolated by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, S1c is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent.
The key intermediate aidehyde depicted as S1c can be reacted with a variety of unsaturated alkenyl anion nucleophiles to provide the C-9 and C-11-protected 13,14-dihydroprostaglandin F1xcex1 derivatives.
The resulting compounds can be isolated, but are generally deprotected using techniques known to one of ordinary skill in the art, and optionally, manipulated at C-1 to provide the desired acid derivative at R1. For example, the condensation of a methyl ester with an amine or a hydroxylamine provides an amide or a hydroxamic acid compound, respectively. After any such manipulation at C-1, the compounds are isolated as the final 13,14dihydro-15-substituted-15-pentanor prostaglandin F1xcex1 derivative, Formula I. Compounds depicted by Formula I are exemplified in Examples 1-12,18, and 20.
Compounds depicted by Formula II can be made directly from intermediate S1c in a manner similar to that for compounds depicted by Formula I substituting the appropriate allene anion. With allene nucleophiles, the reaction is carried out preferably at between xe2x88x9280xc2x0 C. and 0xc2x0 C., more preferably between xe2x88x9280xc2x0 C. and xe2x88x9220xc2x0 C., and most preferably between xe2x88x9280xc2x0 C. and xe2x88x9240xc2x0 C. Preferred bases for the reaction include n-butyl lithium, s-butyl lithium, and t-butyl lithium. The most preferred base is n-butyl lithium. Preferred solvents for the reaction are ether solvents. Preferred solvents include diethyl ether, and tetrahydrofuran. The most preferred solvent is tetrahydrofuran. With heterocyclic nucleophiles, preferred solvents include ethereal solvents. More preferred ethereal solvents include diethyl ether, dibutyl ether and tetrahydrofuran. The most preferred ethereal solvent is tetrahydrofuran. After isolation, similar C-1 manipulations and/or deprotection of the functional groups ensues using techniques known to one of ordinary skill in the art. Compounds depicted by Formula II are exemplified in Examples 13-17 and 19. 
In Scheme 2, R1, Y, and Z are as defined above. The protected alcohol S1b (from Scheme 1) is treated with a hydroborating reagent in an ethereal solvent, followed by oxidative removal of the boron reagent with a suitable oxidant to give a compound of the type S2a. Preferred hydroborating reagents include monochloroborane-dimethylsulfide, diborane, borane-tetrahydrofuran and borane-dimethylsulfide. The most preferred hydroborating reagent is borane-dimethylsulfide. Preferred ethereal solvents include THF and diethyl ether. The most preferred solvent is THF. The reaction is carried out from about 1 to about 24 hours at a temperature of from about xe2x88x9220xc2x0 C. to about +30xc2x0 C. The preferred temperature range is from about 0xc2x0 C. to about +20xc2x0 C. The hydroborated product of this reaction may then be oxidatively removed to the alcohol using alkaline hydrogen peroxide (See. Boranes in Organic Chemistry, H. C. Brown, Cornell University Press, Ithaca, N.Y. 1972, pp. 321-325), which may then be oxidized to either the aldehyde (Wxe2x95x90H) or to the acid (Wxe2x95x90OH) using methods known to one of ordinary skill in the art. Alternatively, the hydroborated product may be directly oxidized to the aldehyde or acid by treatment with chromic acid or a Cr(VI) salt. Such salts include pyridinium chlorochromate (PCC) and dichlorochromate. See Brown, H. C.; Kulkarni, Rao, and Patil, Tetrahedron, 1986, 45515. The preferred method is treatment of the hydroborated product with PCC in dichlororhethane at room temperature. The result of these manipulations is a compound of the type S2a.
The compound S2a is isolaited by methods known to one of ordinary skill in the art. Such methods include, but are not limited to, extraction, solvent evaporation, distillation, and crystallization. Preferably, S2a is purified by flash chromatography on silica gel (Merck, 230-400 mesh) using 20% EtOAc/hexanes as the eluent with 0.1% acetic acid added if Wxe2x95x90OH.
The key intermediate aldehyde depicted as S2a can be reacted with a variety unsaturated carbon nucleophiles to provide the C-9 and C-11-protected 13,14-dihydro-16-tetranor prostaglandin F1xcex1 derivatives of Formula III.
With aromatic and heteroaromatic nucleophiles, the reaction is carried out preferably at between xe2x88x9280xc2x0 C. and 0xc2x0 C., more preferably between xe2x88x9280xc2x0 C. and xe2x88x9220xc2x0 C., and most preferably between xe2x88x9280xc2x0 C. and xe2x88x9240xc2x0 C. Preferred bases for the reaction include n-butyl lithium, s-butyl lithium, lithium diisopropylamide, and t-butyl lithium. The most preferred base is n-butyl lithium. Preferred solvents for the reaction are ether solvents. Preferred solvents include diethyl ether, and tetrahydrofuran. The most preferred solvent is tetrahydrofuran. With heterocyclic nucleophiles, preferred solvents include ethereal solvents. More preferred ethereal solvents include diethyl ether, dibutyl ether and tetrahydrofuran. The most preferred ethereal solvent is tetrahydrofuran.
The resulting alcohol can be isolated, but is generally oxidized as a crude isolate. The oxidation of benzylic alcohols to benzylic ketones is well known in the art. The preferred reagents to effect this reaction include KMnO4, MnO2, chromic acid, Jones"" reagent, Collins"" reagent, and PCC. The most preferred method is oxidation at room temperature in dichloromethane with PCC for about 4 hours. The ketones are isolated by column chromatography using 20% hexanes/ethyl acetate as solvent. The ester is then removed using standard conditions. See Greene and Wuts, Protecting Groups in Organic Synthesis, Wiley Interscience, NY pp.224-276. The free acid is then treated with 2.1 equivalents of a strong nitrogen base to effect deprotonation both of the acid and adjacent to the benzylic ketone. Such bases include LDA. This enolate is reacted with a peroxidizing agent which has the effect of oxidizing the compound to deliver the alpha-hydroxy ketone. Such reagents include meta -chloroperoxybenzoic acid, dimethyl dioxirane, Davis"". reagent and peracetic acid. The crude product may be isolated or the remaining protecting groups may be removed. At this point manipulation of the acid at C-1 may take place. For example, re-esterifying, making the amide, the hydroxamic acid or the sulfonamide using methods known to one of ordinary skill in the art may be performed to yield compounds according to Formula III. Compounds depicted by Formula III are exemplified in Examples 21-30.
Compounds depicted by Formula IV can be made from intermediate S2b. In this case, condensation of the free acid is readily achieved with a variety of alcohols and amines, either by the use of coupling agents such as DCC, or by activating the acid with, for example, oxalyl chloride. Following this is the selective removal of the methyl esters as described in Greene and Wuts, Protecting Groups in Organic Synthesis, Wiley Interscience, NY pp.224-276, and the oxidation of the ester enolates using the same technique described above for the ketone intermediates. Similarly, as described above, the remaining protecting groups are removed and the desired manipulation of C-1 is effected, yielding compounds of Formula IV. Compounds depicted by Formula IV are exemplified in Examples 31-40. 
In Scheme 3, R1 and Z are as defined above. The alkene S1b (from Scheme 1) is treated with an osmium salt and with an optional catalyst reoxidant, preferably N-methyl morpholine N-oxide (NMO), to give the diol. This diol is isolated by extraction and purified by silica gel chromatography. The diol is then oxidized selectively to the alpha hydroxy aidehyde. This may be accomplished in several ways. For example, a selective oxidant such as DMSO-oxalyl chloride may be used. Altematively, the primary alcohol may be selectively protected, then the secondary alcohol protected, then the protection on the primary alcohol may then be removed and the alcohol oxidized as described above in Scheme II. However, the preferred method is the addition of a o-bromo-benzyl bromide protecting group, which can be removed with concomitant oxidation by tributyl tin hydride and like reagents. This technique yields compounds of the type S3a, wherein Pxe2x95x90H. From this step follows the condensation of the aldehyde with an amine to form an imine of the type S3b. Appropriate removal of protecting groups and manipulation of C-1 as stated above in Schemes I and II yields compounds according the Formula V. Compounds depicted by Formula V are exemplified in Examples 41-48.